Abstract The mechanisms responsible for protection against type 1 diabetes (T1D) are not completely understood. Our studies demonstrated that a subset of young T1D-prone non-obese diabetic (NOD) mice have elevated levels of autoantibodies (AAs) to the proteinase inhibitor serpin B13, and that this response correlated with protection from early onset diabetes. Experiments with serpin B13 monoclonal autoantibodies (mAbs) extended these observations by showing that anti-serpin activity is both a biomarker of protection from diabetes and an active contributor to the disease-prevention process. Specifically, we found that injecting serpin B13 mAb impeded islet-associated inflammation in the NOD model and induced the generation of approximately 80 islets per animals in normal Balb/c mice. Our additional analysis of human samples obtained from the Belgian Diabetes Registry demonstrated that early onset T1D is associated with low serpin B13 AA production, suggesting an inverse relationship between the serpin immunological response and the development of clinical diabetes. Importantly, our analysis of TrialNet placebo subjects indicated that baseline serpin antibody is associated with slower decline in residual beta cell function in children with recent onset T1D. Together, our findings in the mouse and humans consistently suggested that antibody response to serpin B13 promotes beneficial outcomes in T1D. To continue translating our findings to humans, we propose a study of individuals at risk for T1D who were followed to the time of disease onset. The successful completion of this project will require examination of serum samples obtained from approximately 600 individuals during their enrollment in the Diabetes Prevention Trial for Type 1 Diabetes (DPT-1). In Aim 1, we will examine subjects with high, intermediate, modest, and low risk for T1D and assess their serological binding activity to SERPIN B13 at baseline. In Aim 2, we will compare serum-binding activities between subjects with an intermediate-to- high risk for T1D who progressed to diabetes versus those that remained diabetes-free. Finally, in Aim 3 we will assess impact of antibodies to serpin B13 on beta cells proliferation in pancreatic islets isolated from humans. Serpin AAs will be detected with a Luminex-based technology that was developed in our laboratory and validated in collaboration with the Core for Assay Validaion (CAV) at the Benaroya Research Institute. This study will help to clarify whether humoral immunity to serpin molecules could be a biomarker of homeostasis resulting in improved beta cell health in the setting of autoimmune inflammation in human patients. It will also help us to verify the hypothesis that serpin B13 mAbs can be therapeutically beneficial by enhancing immunity against serpins.